Myorisan

Soft gelatin capsules, 10 mg (pale yellow), imprinted in black ink with “V10”. Boxes of 30 containing 3 Prescription Packs of 10 capsules (NDC 61748-301-13). Boxes of 100 containing 10 Prescription Packs of 10 capsules (NDC 61748-301-11). Soft gelatin capsules, 20 mg (white to slight pink), imprinted in black ink with “V20”. Boxes of 30 containing 3 Prescription Packs of 10 capsules (NDC 61748-302-13). Boxes of 100 containing 10 Prescription Packs of 10 capsules (NDC 61748-302-11). Soft gelatin capsules, 30 mg (pink), imprinted in black ink with “V30”. Boxes of 30 containing 3 Prescription Packs of 10 capsules (NDC 61748-303-13). Boxes of 100 containing 10 Prescription Packs of 10 capsules (NDC 61748-303-11). Soft gelatin capsules, 40 mg (orange), imprinted in black ink with “V40”. Boxes of 30 containing 3 Prescription Packs of 10 capsules (NDC 61748-304-13). Boxes of 100 containing 10 Prescription Packs of 10 capsules (NDC 61748-304-11).

Storage

Store at 20°-25°C (68° to 77°F).. Protect from light.

Patient Information/Informed Consent About Birth Defects (for female patients who can get pregnant)

To be completed by the patient (and her parent or guardian* if patient is under age 18) and signed by her doctor.

Read each item below and initial in the space provided to show that you understand each item and agree to follow your doctor's instructions. Do not sign this consent and do not take isotretinoin if there is anything that you do not understand.

*A parent or guardian of a minor patient (under age 18) must also read and initial each item before signing the consent.

______________________________________________________________

(Patient's Name)

1. I understand that there is a very high chance that my unborn baby could have severe birth defects if I am pregnant or become pregnant while taking isotretinoin. This can happen with any amount and even if taken for short periods of time. This is why I must not be pregnant while taking isotretinoin.

Initial: ______

2. I understand that I must not get pregnant one month before, during the entire time of my treatment, and for one month after the end of my treatment with isotretinoin.

Initial: ______

3. I understand that I must avoid sexual intercourse completely, or I must use two separate, effective forms of birth control (contraception) at the same time. The only exceptions are if I have had surgery to remove the uterus (a hysterectomy) or both of my ovaries (bilateral oophorectomy), or my doctor has medically confirmed that I am post-menopausal.

Initial: ______

4. I understand that hormonal birth control products are among the most effective forms of birth control. Combination birth control pills and other hormonal products include skin patches, shots, under-the-skin implants, vaginal rings, and intrauterine devices (IUDs). Any form of birth control can fail. That is why I must use two different birth control methods at the same time, starting one month before, during, and for one month after stopping therapy every time I have sexual intercourse, even if one of the methods I choose is hormonal birth control.

Initial: ______

5. I understand that the following are effective forms of birth control:

Primary forms

• tying my tubes (tubal sterilization)
• partner's vasectomy
• intrauterine device
• hormonal (combination birth control pills, skin patches, shots, under-the-skin implants or vaginal ring)

Secondary forms

Barrier:

• male latex condom with or without spermicide
• diaphragm with spermicide
• cervical cap with spermicide

Other:

• vaginal sponge (contains spermicide)

A diaphragm and cervical cap must each be used with spermicide, a special cream that kills sperm.

I understand that at least one of my two forms of birth control must be a primary method.

Initial: ______

6. I will talk with my doctor about any medicines including herbal products I plan to take during my isotretinoin treatment because hormonal birth control methods may not work if I am taking certain medicines or herbal products.

Initial: ______

7. I may receive a free birth control counseling session from a doctor or other family planning expert. My isotretinoin doctor can give me an isotretinoin Patient Referral Form for this free consultation.

Initial: ______

8. I must begin using the birth control methods I have chosen as described above at least one month before I start taking isotretinoin.

Initial: ______

9. I cannot get my first prescription for isotretinoin unless my doctor has told me that I have two negative pregnancy test results. The first pregnancy test should be done when my doctor decides to prescribe isotretinoin. The second pregnancy test must be done in a lab during the first 5 days of my menstrual period right before starting isotretinoin therapy treatment, or as instructed by my doctor. I will then have one pregnancy test; in a lab.

• every month during treatment
• at the end of treatment
• and 1 month after stopping treatment

I must not start taking isotretinoin until I am sure that I am not pregnant, have negative results from two pregnancy tests, and the second test has been done in a lab.

Initial: ______

10. I have read and understand the materials my doctor has provided to me, including The Ipledge Program Guide for Isotretinoin for Female Patients Who Can Get Pregnant, The iPLEDGE Birth Control Workbook and The iPLEDGE Program Patient Introductory Brochure.

My doctor provided me and asked me to watch a video about birth control and a video about birth defects and isotretinoin.

I was told about a private counseling line that I may call for more information about birth control. I have received information on emergency birth control.

Initial: ______

11. I must stop taking isotretinoin right away and call my doctor if I get pregnant, miss my expected menstrual period, stop using birth control, or have sexual intercourse without using my two birth control methods at any time.

Initial: ______

12. My doctor provided me information about the purpose and importance of providing information to the iPLEDGE Program should I become pregnant while taking isotretinoin or within one month of the last dose. I understand that if I become pregnant, information about my pregnancy, my health, and my baby's health may be shared with the makers of isotretinoin, authorized parties who maintain the iPLEDGE Program for the makers of isotretinoin and government health regulatory authorities.

Initial: ______

13. I understand that being qualified to receive isotretinoin in the iPLEDGE Program means that I:

• have had two negative urine or blood pregnancy tests before receiving the first isotretinoin prescription. The second test must be done in a lab. I must have a negative result from a urine or blood pregnancy test done in a lab repeated each month before I receive another isotretinoin prescription.
• have chosen and agreed to use two forms of effective birth control at the same time. At least one method must be a primary form of birth control, unless I have chosen never to have sexual contact with a male (abstinence), or I have undergone a hysterectomy. I must use two forms of birth control for at least one month before I start isotretinoin therapy, during therapy, and for one month after stopping therapy. I must receive counseling, repeated on a monthly basis, about birth control and behaviors associated with an increased risk of pregnancy.
• have signed a Patient Information/Informed Consent About Birth Defects (for female patients who can get pregnant) that contains warnings about the chance of possible birth defects if I am pregnant or become pregnant and my unborn baby is exposed to isotretinoin.
• have been informed of and understand the purpose and importance of providing information to the iPLEDGE Program should I become pregnant while taking isotretinoin or within 1 month of the last dose.
• have interacted with the iPLEDGE Program before starting isotretinoin and on a monthly basis to answer questions on the program requirements and to enter my two chosen forms of birth control.

Initial: ______

My doctor has answered all my questions about isotretinoin and I understand that it is my responsibility not to get pregnant one month before, during isotretinoin treatment, or for one month after I s top taking isotretinoin.

Initial: ______

I now authorize my doctor ________________ to begin my treatment with isotretinoin.

Patient Signature:___________________________________ Date: ______

Parent/Guardian Signature (if under age 18):________________ Date:______

Please print: Patient Name and Address_______________________________

________________________________ Telephone ______________________

I have fully explained to the patient, __________________, the nature and purpose of the treatment described above and the risks to females of reproductive potential. I have asked the patient if she has any questions regarding her treatment with isotretinoin and have answered those questions to the best of my ability.

Doctor Signature: ____________________________________ Date: ______

PLACE THE ORIGINAL SIGNED DOCUMENTS IN THE PATIENT'S MEDICAL RECORD. PLEASE PROVIDE A COPY TO THE PATIENT.

Patient Information/Informed Consent (for all patients ):

To be completed by patient (and parent or guardian if patient is under age 18) and signed by the doctor.

Read each item below and initial in the space provided if you understand each item and agree to follow your doctor's instructions. A parent or guardian of a patient under age 18 must also read and understand each item before signing the agreement.

Do not sign this agreement and do not take isotretinoin if there is anything that you do not understand about all the information you have received about using isotretinoin.

1. I, ______________________________________________________________,

(Patient's Name)

understand that isotretinoin is a medicine used to treat severe nodular acne that cannot be cleared up by any other acne treatments, including antibiotics. In severe nodular acne, many red, swollen, tender lumps form in the skin. If untreated, severe nodular acne can lead to permanent scars.

Initials: ______

2. My doctor has told me about my choices for treating my acne.

Initials: ______

3. I understand that there are serious side effects that may happen while I am taking isotretinoin. These have been explained to me. These side effects include serious birth defects in babies of pregnant patients. [Note: There is a second Patient Information/Informed Consent About Birth Defects (for female patients who can get pregnant)].

Initials: ______

4. I understand that some patients, while taking isotretinoin or soon after stopping isotretinoin, have become depressed or developed other serious mental problems. Symptoms of depression include sad, “anxious” or empty mood, irritability, acting on dangerous impulses, anger, loss of pleasure or interest in social or sports activities, sleeping too much or too little, changes in weight or appetite, school or work performance going down, or trouble concentrating. Some patients taking isotretinoin have had thoughts about hurting themselves or putting an end to their own lives (suicidal thoughts). Some people tried to end their own lives. And some people have ended their own lives. There were reports that some of these people did not appear depressed. There have been reports of patients on isotretinoin becoming aggressive or violent. No one knows if isotretinoin caused these behaviors or if they would have happened even if the person did not take isotretinoin. Some people have had other signs of depression while taking isotretinoin (see #7 below).

Initials: ______

5. Before I start taking isotretinoin, I agree to tell my doctor if I have ever had symptoms of depression (see #7 below), been psychotic, attempted suicide, had any other mental problems, or take medicine for any of these problems. Being psychotic means having a loss of contact with reality, such as hearing voices or seeing things that are not there.

Initials: ______

6. Before I start taking isotretinoin, I agree to tell my doctor if, to the best of my knowledge, anyone in my family has ever had symptoms of depression, been psychotic, attempted suicide, or had any other serious mental problems.

Initials: ______

7. Once I start taking isotretinoin, I agree to stop using isotretinoin and tell my doctor right away if any of the following signs and symptoms of depression or psychosis happen. I:

• Start to feel sad or have crying spells
• Lose interest in activities I once enjoyed
• Sleep too much or have trouble sleeping
• Become more irritable, angry, or aggressive than usual (for example, temper outbursts, thoughts of violence)
• Have a change in my appetite or body weight
• Have trouble concentrating
• Withdraw from my friends or family
• Feel like I have no energy
• Have feelings of worthlessness or guilt
• Start having thoughts about hurting myself or taking my own life (suicidal thoughts)
• Start acting on dangerous impulses
• Start seeing or hearing things that are not real

Initials: ______

8. I agree to return to see my doctor every month I take isotretinoin to get a new prescription for isotretinoin, to check my progress, and to check for signs of side effects.

Initials: ______

9. Isotretinoin will be prescribed just for me - I will not share isotretinoin with other people because it may cause serious side effects, including birth defects.

Initials: ______

10. I will not give blood while taking isotretinoin or for 1 month after I stop taking isotretinoin. I understand that if someone who is pregnant gets my donated blood, her baby may be exposed to isotretinoin and may be born with serious birth defects.

Initials: ______

11. I have read The iPLEDGE Program Patient Introductory Brochure, and other materials my provider provided me containing important safety information about isotretinoin. I understand all the information I received.

Initials: ______

12. My doctor and I have decided I should take isotretinoin. I understand that I must be qualified in the iPLEDGE Program to have my prescription filled each month. I understand that I can stop taking isotretinoin at any time. I agree to tell my doctor if I stop taking isotretinoin.

Initials: ______

I now allow my doctor ___________________________ to begin my treatment with isotretinoin.

Patient Signature: ____________________________________ Date: ______

Parent/Guardian Signature (if under age 18): _______________ Date: ______

Patient Name (print) ___________________________________

Patient Address ___________________________ Telephone (___.___.___)

_____________________________________________________________

I have:

• fully explained to the patient, __________________, the nature and purpose of isotretinoin treatment, including its benefits and risks
• provided the patient with the appropriate educational materials, The iPLEDGE Program Patient Introductory Brochure and asked the patient if he/she has any questions regarding his/her treatment with isotretinoin
• answered those questions to the best of my ability

Doctor Signature: _________________________________ Date: ______

PLACE THE ORIGINAL SIGNED DOCUMENTS IN THE PATIENT'S MEDICAL RECORD. PLEASE PROVIDE A COPY TO THE PATIENT.

REFERENCES

1. Peck GL, Olsen TG, Yoder FW, et al. Prolonged remissions of cystic and conglobate acne with 13-cis-retinoic acid. N Engl J Med 300:329-333, 1979.

2. Pochi PE, Shalita AR, Strauss JS, Webster SB. Report of the consensus conference on acne classification. J Am Acad Dermatol 24:495-500, 1991.

3. Farrell LN, Strauss JS, Stranieri AM. The treatment of severe cystic acne with 13-cis-retinoic acid: evaluation of sebum production and the clinical response in a multiple-dose trial. J Am Acad Dermatol 3:602-611, 1980.

4. Jones H, Blanc D, Cunliffe WJ. 13-cis-retinoic acid and acne. Lancet 2:1048-1049, 1980.

8. Strauss JS, Rapini RP, Shalita AR, et al. Isotretinoin therapy for acne: results of a multicenter doseresponse study. J Am Acad Dermatol 10:490-496, 1984.

Distributed by: VersaPharm Inc. - An Akorn Company, Lake Forest, IL 60045. Revised: Sep 2015

Severe Recalcitrant Nodular Acne

Myorisan is indicated for the treatment of severe recalcitrant nodular acne. Nodules are inflammatory lesions with a diameter of 5 mm or greater. The nodules may become suppurative or hemorrhagic. “Severe,” by definition,² means “many” as opposed to “few or several” nodules. Because of significant adverse effects associated with its use, Myorisan should be reserved for patients with severe nodular acne who are unresponsive to conventional therapy, including systemic antibiotics. In addition, Myorisan is indicated only for those female patients who are not pregnant, because Myorisan can cause severe birth defects (see BOXED CONTRAINDICATIONS AND WARNINGS).

A single course of therapy for 15 to 20 weeks has been shown to result in complete and prolonged remission of disease in many patients.^1,3,4 If a second course of therapy is needed, it should not be initiated until at least 8 weeks after completion of the first course, because experience has shown that patients may continue to improve while off Myorisan. The optimal interval before retreatment has not been defined for patients who have not completed skeletal growth (see WARNINGS: Skeletal: Bone Mineral Density, Hyperostosis, Premature Epiphyseal Closure).

Myorisan should be administered with a meal (see PATIENT INFORMATION).

The recommended dosage range for Myorisan is 0.5 to 1 mg/kg/day given in two divided doses with food for 15 to 20 weeks. In studies comparing 0.1, 0.5, and 1 mg/kg/day,⁸ it was found that all dosages provided initial clearing of disease, but there was a greater need for retreatment with the lower dosages. During treatment, the dose may be adjusted according to response of the disease and/or the appearance of clinical side effects - some of which may be dose related. Adult patients whose disease is very severe with scarring or is primarily manifested on the trunk may require dose adjustments up to 2 mg/kg/day, as tolerated. Failure to take Myorisan with food will significantly decrease absorption. Before upward dose adjustments are made, the patients should be questioned about their compliance with food instructions.

The safety of once daily dosing with Myorisan has not been established. Once daily dosing is not recommended.

If the total nodule count has been reduced by more than 70% prior to completing 15 to 20 weeks of treatment, the drug may be discontinued. After a period of 2 months or more off therapy, and if warranted by persistent or recurring severe nodular acne, a second course of therapy may be initiated.

The optimal interval before retreatment has not been defined for patients who have not completed skeletal growth. Long-term use of Myorisan, even in low doses, has not been studied, and is not recommended. It is important that Myorisan be given at the recommended doses for no longer than the recommended duration. The effect of long-term use of Myorisan on bone loss is unknown (see WARNINGS: Skeletal: Bone Mineral Density, Hyperostosis, and Premature Epiphyseal Closure).

Contraceptive measures must be followed for any subsequent course of therapy (see PRECAUTIONS).

Table 4 : Myorisan Dosing by Body Weight (Based on Administration With Food)

INFORMATION FOR PHARMACISTS

Access the iPLEDGE system via the internet (www.ipledgeprogram.com) or telephone (1-866- 495-0654) to obtain an authorization and the “do not dispens e to patient after” date. Myorisan must only be dispensed in no more than a 30-day supply.

REFILLS REQUIRE A NEW PRESCRIPTION AND A NEW AUTHORIZATION FROM THE iPLEDGE SYSTEM.

A Myorisan Medication Guide must be given to the patient each time Myorisan is dispensed, as required by law. This Myorisan Medication Guide is an important part of the risk management program for the patient.

SIDE EFFECTS

Clinical Trials And Postmarketing Surveillance

The adverse reactions listed below reflect the experience from investigational studies of Myorisan, and the postmarketing experience. The relationship of some of these events to Myorisan therapy is unknown. Many of the side effects and adverse reactions seen in patients receiving Myorisan are similar to those described in patients taking very high doses of vitamin A (dryness of the skin and mucous membranes, eg, of the lips, nasal passage, and eyes).

Dose Relationship

Cheilitis and hypertriglyceridemia are usually dose related. Most adverse reactions reported in clinical trials were reversible when therapy was discontinued; however, some persisted after cessation of therapy (see WARNINGS).

Body as a Whole

allergic reactions, including vasculitis, systemic hypersensitivity (see PRECAUTIONS: Hypersensitivity), edema, fatigue, lymphadenopathy, weight loss

Cardiovascular

palpitation, tachycardia, vascular thrombotic disease, stroke

Endocrine/Metabolic

hypertriglyceridemia (see WARNINGS: Lipids ), alterations in blood sugar levels (see PRECAUTIONS: Laboratory Tests).

Gastrointestinal

inflammatory bowel disease (see WARNINGS: Inflammatory Bowel Disease), hepatitis (see WARNINGS: Hepatotoxicity), pancreatitis (see WARNINGS: Lipids ), bleeding and inflammation of the gums, colitis, esophagitis/esophageal ulceration, ileitis, nausea, other nonspecific gastrointestinal symptoms.

Hematologic

allergic reactions (see PRECAUTIONS: Hypersensitivity), anemia, thrombocytopenia, neutropenia, rare reports of agranulocytosis (see PATIENT INFORMATION). See PRECAUTIONS: Laboratory Tests for other hematological parameters.

Musculoskeletal

skeletal hyperostosis, calcification of tendons and ligaments, premature epiphyseal closure, decreases in bone mineral density (see WARNINGS: Skeletal), musculoskeletal symptoms (sometimes severe) including back pain, myalgia, and arthralgia (see PATIENT INFORMATION), transient pain in the chest (see PATIENT INFORMATION), arthritis, tendonitis, other types of bone abnormalities, elevations of CPK/rare reports of rhabdomyolysis (see PRECAUTIONS: Laboratory Tests ).

Neurological

pseudotumor cerebri (see WARNINGS: Pseudotumor Cerebri), dizziness, drowsiness, headache, insomnia, lethargy, malaise, nervousness, paresthesias, seizures, stroke, syncope, weakness.

Psychiatric

suicidal ideation, suicide attempts, suicide, depression, psychosis, aggression, violent behaviors (see WARNINGS: Psychiatric Disorders), emotional instability.

Of the patients reporting depression, some reported that the depression subsided with discontinuation of therapy and recurred with reinstitution of therapy.

Reproductive System

Abnormal menses.

Respiratory

bronchospasms (with or without a history of asthma), respiratory infection, voice alteration

Skin and Appendages

acne fulminans, alopecia (which in some cases persists), bruising, cheilitis (dry lips), dry mouth, dry nose, dry skin, epistaxis, eruptive xanthomas,⁷ erythema multiforme, flushing, fragility of skin, hair abnormalities, hirsutism, hyperpigmentation and hypopigmentation, infections (including disseminated herpes simplex), nail dystrophy, paronychia, peeling of palms and soles, photoallergic /photosensitizing reactions, pruritus, pyogenic granuloma, rash (including facial erythema, seborrhea, and eczema), Stevens-Johnson syndrome, sunburn susceptibility increased, sweating, toxic epidermal necrolysis, urticaria, vasculitis (including Wegener's granulomatosis; see PRECAUTIONS: Hypersensitivity), abnormal wound healing (delayed healing or exuberant granulation tissue with crusting; see PATIENT INFORMATION)

Special Senses

Hearing

hearing impairment (see WARNINGS: Hearing Impairment), tinnitus.

Vision

corneal opacities (see WARNINGS: Corneal Opacities ), decreased night vision which may persist (see WARNINGS: Decreased Night Vision), cataracts, color vision disorder, conjunctivitis, dry eyes, eyelid inflammation, keratitis, optic neuritis, photophobia, visual disturbances

Urinary System

glomerulonephritis (see PRECAUTIONS: Hypersensitivity), nonspecific urogenital findings (see PRECAUTIONS: Laboratory Tests for other urological parameters)

Laboratory

Elevation of plasma triglycerides (see WARNINGS: Lipids ), decrease in serum high-density lipoprotein (HDL) levels, elevations of serum cholesterol during treatment

Increased alkaline phosphatase, SGOT (AST), SGPT (ALT), GGTP or LDH (see WARNINGS: Hepatotoxicity)

Elevation of fasting blood sugar, elevations of CPK (see PRECAUTIONS: Laboratory Tests), hyperuricemia

Decreases in red blood cell parameters, decreases in white blood cell counts (including severe neutropenia and rare reports of agranulocytosis; see PATIENT INFORMATION), elevated sedimentation rates, elevated platelet counts, thrombocytopenia

White cells in the urine, proteinuria, microscopic or gross hematuria

REFERENCES

7. Dicken CH, Connolly SM. Eruptive xanthomas associated with isotretinoin (13-cis-retinoic acid). Arch Dermatol 116:951-952, 1980.

DRUG INTERACTIONS

• Vitamin A: Because of the relationship of Myorisan to vitamin A, patients should be advised against taking vitamin supplements containing vitamin A to avoid additive toxic effects.
• Tetracyclines: Concomitant treatment with Myorisan and tetracyclines should be avoided because Myorisan use has been associated with a number of cases of pseudotumor cerebri (benign intracranial hypertension), some of which involved concomitant use of tetracyclines.
• Micro-dosed Progesterone Preparations: Micro-dosed progesterone preparations (“minipills” that do not contain an estrogen) may be an inadequate method of contraception during Myorisan therapy. Although other hormonal contraceptives are highly effective, there have been reports of pregnancy from female patients who have used combined oral contraceptives, as well as transdermal patch/injectable/implantable/vaginal ring hormonal birth control products. These reports are more frequent for female patients who use only a single method of contraception. It is not known if hormonal contraceptives differ in their effectiveness when used with Myorisan. Therefore, it is critically important for females of reproductive potential to select and commit to use two forms of effective contraception simultaneously, at least one of which must be a primary form (see PRECAUTIONS).
• Norethindrone/ethinylestradiol: In a study of 31 premenopausal female patients with severe recalcitrant nodular acne receiving OrthoNovum® 7/7/7 Tablets as an oral contraceptive agent, Myorisan at the recommended dose of 1 mg/kg/day, did not induce clinically relevant changes in the pharmacokinetics of ethinyl estradiol and norethindrone and in the serum levels of progesterone, follicle-stimulating hormone (FSH) and luteinizing hormone (LH). Prescribers are advised to consult the package insert of medication administered concomitantly with hormonal contraceptives, since some medications may decrease the effectiveness of these birth control products.
• St. John's Wort: Myorisan use is associated with depression in some patients (see WARNINGS: Psychiatric Disorders and ADVERSE REACTIONS: Psychiatric). Patients should be prospectively cautioned not to self-medicate with the herbal supplement St. John's Wort because a possible interaction has been suggested with hormonal contraceptives based on reports of breakthrough bleeding on oral contraceptives shortly after starting St. John's Wort. Pregnancies have been reported by users of combined hormonal contraceptives who also used some form of St. John's Wort.
• Phenytoin: Myorisan has not been shown to alter the pharmacokinetics of phenytoin in a study in seven healthy volunteers. These results are consistent with the in vitro finding that neither isotretinoin nor its metabolites induce or inhibit the activity of the CYP 2C9 human hepatic P450 enzyme. Phenytoin is known to cause osteomalacia. No formal clinical studies have been conducted to assess if there is an interactive effect on bone loss between phenytoin and Myorisan. Therefore, caution should be exercised when using these drugs together.
• Systemic Corticosteroids: Systemic corticosteroids are known to cause osteoporosis. No formal clinical studies have been conducted to assess if there is an interactive effect on bone loss between systemic corticosteroids and Myorisan. Therefore, caution should be exercised when using these drugs together.

Laboratory Tests

Pregnancy Test

• Females of reproductive potential must have had two negative urine or serum pregnancy tests with a sensitivity of at least 25 mIU/mL before receiving the initial Myorisan prescription. The first test (a screening test) is obtained by the prescriber when the decision is made to pursue qualification of the patient for Myorisan. The second pregnancy test (a confirmation test) must be done in a CLIA-certified laboratory. The interval between the two tests must be at least 19 days.
• For patients with regular menstrual cycles, the second pregnancy test must be done during the first 5 days of the menstrual period immediately preceding the beginning of Myorisan therapy and after the patient has used 2 forms of contraception for 1 month.
• For patients with amenorrhea, irregular cycles, or using a contraceptive method that precludes withdrawal bleeding, the second pregnancy test must be done immediately preceding the beginning of Myorisan therapy and after the patient has used 2 forms of contraception for 1 month.
• Each month of therapy, patients must have a negative result from a urine or serum pregnancy test. A pregnancy test must be repeated each month, in a CLIA-certified laboratory, prior to the female patient receiving each prescription.
  • Lipids: Pretreatment and follow-up blood lipids should be obtained under fasting conditions. After consumption of alcohol, at least 36 hours should elapse before these determinations are made. It is recommended that these tests be performed at weekly or biweekly intervals until the lipid response to Myorisan is established. The incidence of hypertriglyceridemia is one patient in four on Myorisan therapy (see WARNINGS: Lipids ).
  • Liver Function Tests: Since elevations of liver enzymes have been observed during clinical trials, and hepatitis has been reported, pretreatment and follow-up liver function tests should be performed at weekly or biweekly intervals until the response to Myorisan has been established (see WARNINGS: Hepatotoxicity).
  • Glucose: Some patients receiving Myorisan have experienced problems in the control of their blood sugar. In addition, new cases of diabetes have been diagnosed during Myorisan therapy, although no causal relationship has been established.
  • CPK: Some patients undergoing vigorous physical activity while on Myorisan therapy have experienced elevated CPK levels; however, the clinical significance is unknown. There have been rare postmarketing reports of rhabdomyolysis, some associated with strenuous physical activity. In a clinical trial of 217 pediatric patients (12 to 17 years) with severe recalcitrant nodular acne, transient elevations in CPK were observed in 12% of patients, including those undergoing strenuous physical activity in association with reported musculoskeletal adverse events such as back pain, arthralgia, limb injury, or muscle sprain. In these patients, approximately half of the CPK elevations returned to normal within 2 weeks and half returned to normal within 4 weeks. No cases of rhabdomyolysis were reported in this trial.

Category X. See BOXED CONTRAINDICATIONS AND WARNINGS.

Clinical Trials And Postmarketing Surveillance

The adverse reactions listed below reflect the experience from investigational studies of Myorisan, and the postmarketing experience. The relationship of some of these events to Myorisan therapy is unknown. Many of the side effects and adverse reactions seen in patients receiving Myorisan are similar to those described in patients taking very high doses of vitamin A (dryness of the skin and mucous membranes, eg, of the lips, nasal passage, and eyes).

Dose Relationship

Cheilitis and hypertriglyceridemia are usually dose related. Most adverse reactions reported in clinical trials were reversible when therapy was discontinued; however, some persisted after cessation of therapy (see WARNINGS).

Body as a Whole

allergic reactions, including vasculitis, systemic hypersensitivity (see PRECAUTIONS: Hypersensitivity), edema, fatigue, lymphadenopathy, weight loss

Cardiovascular

palpitation, tachycardia, vascular thrombotic disease, stroke

Endocrine/Metabolic

hypertriglyceridemia (see WARNINGS: Lipids ), alterations in blood sugar levels (see PRECAUTIONS: Laboratory Tests).

Gastrointestinal

inflammatory bowel disease (see WARNINGS: Inflammatory Bowel Disease), hepatitis (see WARNINGS: Hepatotoxicity), pancreatitis (see WARNINGS: Lipids ), bleeding and inflammation of the gums, colitis, esophagitis/esophageal ulceration, ileitis, nausea, other nonspecific gastrointestinal symptoms.

Hematologic

allergic reactions (see PRECAUTIONS: Hypersensitivity), anemia, thrombocytopenia, neutropenia, rare reports of agranulocytosis (see PATIENT INFORMATION). See PRECAUTIONS: Laboratory Tests for other hematological parameters.

Musculoskeletal

skeletal hyperostosis, calcification of tendons and ligaments, premature epiphyseal closure, decreases in bone mineral density (see WARNINGS: Skeletal), musculoskeletal symptoms (sometimes severe) including back pain, myalgia, and arthralgia (see PATIENT INFORMATION), transient pain in the chest (see PATIENT INFORMATION), arthritis, tendonitis, other types of bone abnormalities, elevations of CPK/rare reports of rhabdomyolysis (see PRECAUTIONS: Laboratory Tests ).

Neurological

pseudotumor cerebri (see WARNINGS: Pseudotumor Cerebri), dizziness, drowsiness, headache, insomnia, lethargy, malaise, nervousness, paresthesias, seizures, stroke, syncope, weakness.

Psychiatric

suicidal ideation, suicide attempts, suicide, depression, psychosis, aggression, violent behaviors (see WARNINGS: Psychiatric Disorders), emotional instability.

Of the patients reporting depression, some reported that the depression subsided with discontinuation of therapy and recurred with reinstitution of therapy.

Reproductive System

Abnormal menses.

Respiratory

bronchospasms (with or without a history of asthma), respiratory infection, voice alteration

Skin and Appendages

acne fulminans, alopecia (which in some cases persists), bruising, cheilitis (dry lips), dry mouth, dry nose, dry skin, epistaxis, eruptive xanthomas,⁷ erythema multiforme, flushing, fragility of skin, hair abnormalities, hirsutism, hyperpigmentation and hypopigmentation, infections (including disseminated herpes simplex), nail dystrophy, paronychia, peeling of palms and soles, photoallergic /photosensitizing reactions, pruritus, pyogenic granuloma, rash (including facial erythema, seborrhea, and eczema), Stevens-Johnson syndrome, sunburn susceptibility increased, sweating, toxic epidermal necrolysis, urticaria, vasculitis (including Wegener's granulomatosis; see PRECAUTIONS: Hypersensitivity), abnormal wound healing (delayed healing or exuberant granulation tissue with crusting; see PATIENT INFORMATION)

Special Senses

Hearing

hearing impairment (see WARNINGS: Hearing Impairment), tinnitus.

Vision

corneal opacities (see WARNINGS: Corneal Opacities ), decreased night vision which may persist (see WARNINGS: Decreased Night Vision), cataracts, color vision disorder, conjunctivitis, dry eyes, eyelid inflammation, keratitis, optic neuritis, photophobia, visual disturbances

Urinary System

glomerulonephritis (see PRECAUTIONS: Hypersensitivity), nonspecific urogenital findings (see PRECAUTIONS: Laboratory Tests for other urological parameters)

Laboratory

Elevation of plasma triglycerides (see WARNINGS: Lipids ), decrease in serum high-density lipoprotein (HDL) levels, elevations of serum cholesterol during treatment

Increased alkaline phosphatase, SGOT (AST), SGPT (ALT), GGTP or LDH (see WARNINGS: Hepatotoxicity)

Elevation of fasting blood sugar, elevations of CPK (see PRECAUTIONS: Laboratory Tests), hyperuricemia

Decreases in red blood cell parameters, decreases in white blood cell counts (including severe neutropenia and rare reports of agranulocytosis; see PATIENT INFORMATION), elevated sedimentation rates, elevated platelet counts, thrombocytopenia

White cells in the urine, proteinuria, microscopic or gross hematuria

REFERENCES

7. Dicken CH, Connolly SM. Eruptive xanthomas associated with isotretinoin (13-cis-retinoic acid). Arch Dermatol 116:951-952, 1980.

Absorption

Due to its high lipophilicity, oral absorption of isotretinoin is enhanced when given with a high-fat meal. In a crossover study, 74 healthy adult subjects received a single 80 mg oral dose (2 x 40 mg capsules) of Myorisan under fasted and fed conditions. Both peak plasma concentration (Cmax) and the total exposure (AUC) of isotretinoin were more than doubled following a standardized high-fat meal when compared with Myorisan given under fasted conditions (see Table 2). The observed elimination half-life was unchanged. This lack of change in half-life suggests that food increases the bioavailability of isotretinoin without altering its disposition. The time to peak concentration (Tmax) was also increased with food and may be related to a longer absorption phase. Therefore, Myorisan capsules should always be taken with food (see DOSAGE AND ADMINISTRATION). Clinical studies have shown that there is no difference in the pharmacokinetics of isotretinoin between patients with nodular acne and healthy subjects with normal skin.

Table 2 : Pharmacokinetic Parameters of Is otretinoin Mean (%CV), N=74

Distribution

Isotretinoin is more than 99.9% bound to plasma proteins, primarily albumin.

Metabolism

Following oral administration of isotretinoin, at least three metabolites have been identified in human plasma: 4-oxo-isotretinoin, retinoic acid (tretinoin), and 4-oxo-retinoic acid (4-oxo-tretinoin). Retinoic acid and 13-cis-retinoic acid are geometric isomers and show reversible interconversion. The administration of one isomer will give rise to the other. Isotretinoin is also irreversibly oxidized to 4-oxo-isotretinoin, which forms its geometric isomer 4-oxo-tretinoin.

After a single 80 mg oral dose of Myorisan to 74 healthy adult subjects, concurrent administration of food increased the extent of formation of all metabolites in plasma when compared to the extent of formation under fasted conditions.

All of these metabolites possess retinoid activity that is in some in vitro models more than that of the parent isotretinoin. However, the clinical significance of these models is unknown. After multiple oral dose administration of isotretinoin to adult cystic acne patients ( ≥ 18 years), the exposure of patients to 4-oxo-isotretinoin at steady-state under fasted and fed conditions was approximately 3.4 times higher than that of isotretinoin.

In vitro studies indicate that the primary P450 isoforms involved in isotretinoin metabolism are 2C8, 2C9, 3A4, and 2B6. Isotretinoin and its metabolites are further metabolized into conjugates, which are then excreted in urine and feces.

Elimination

Following oral administration of an 80 mg dose of ¹⁴C- isotretinoin as a liquid suspension, ¹⁴C- activity in blood declined with a half-life of 90 hours. The metabolites of isotretinoin and any conjugates are ultimately excreted in the feces and urine in relatively equal amounts (total of 65% to 83%). After a single 80 mg oral dose of Myorisan to 74 healthy adult subjects under fed conditions, the mean ±SD elimination half-lives (tmax) of isotretinoin and 4-oxo-isotretinoin were 21 ± 8.2 hours and 24 ± 5.3 hours, respectively. After both single and multiple doses, the observed accumulation ratios of isotretinoin ranged from 0.9 to 5.43 in patients with cystic acne.